For the relief of severe pain in adults, adolescents (aged 13-18 years) and children (aged 1-12 years).

Posology
Adults: Recommended dose 10-20 mg (8-16 drops) every 4 hours.
Maximum daily dose: 120 mg per day.
Paediatric population:
Adolescents 13 - 18 years: Recommended dose 5-20 mg (4-16 drops) every 4 hours.
Maximum daily dose: 120 mg per day
Children 6-12 years: Recommended dose 5-10 mg (4-8 drops) every 4 hours.
Maximum daily dose: 60 mg per day
Children 1-5 years: Recommended dose 5 mg (4 drops) every 4 hours.
Maximum daily dose: 30 mg per day.
Children under 1 year: Not recommended.

Under medical control the dose can be increased depending on the severity of pain and depending on the previous use of analgesics.
Special populations:
Reductions in dosage may be appropriate in the elderly and in patients with chronic hepatic disease (for acute hepatic disease see section 4.3), renal impairment, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock or where sedation is undesirable.
Discontinuation of therapy
Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with Oramorph in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).
Method of Administration
For oral use
The dose is determined by counting the drops from the 20 ml bottle (1 drop = 1.25 mg morphine sulfate):
4 drops = 5 mg morphine sulfate
8 drops = 10 mg morphine sulfate
16 drops = 20 mg morphine sulfate
24 drops = 30 mg morphine sulfate
After withdrawal of the medicine the bottle is closed again with the screw closure.
The required dose may be added to a soft drink immediately prior to administration..
Correspondence between the different routes of administration:
When patients are transferred from other morphine preparations to Oramorph dosage titration may be appropriate.
Morphine sulfate is readily absorbed from the gastro-intestinal tract following oral administration. However, when oral Oramorph preparations are used in place of parenteral morphine, a 50 % to 100 % increase in dosage is usually required in order to achieve the same level of analgesia.

Oramorph is contraindicated in: • patients known to be hypersensitivity to morphine sulfate or to any of the excipients listed in section 6.1 • respiratory insufficiency or respiratory depression, obstructive airways disease • paralytic ileus (see section 4.4) • acute liver disorders (hepatitis, hepatic porphyria) • acute alcohol intoxication • head injury and conditions with increased intracranial pressure (see section 4.4) • coma (see section 4.4) • convulsive disorders • concurrent administration with monoamine oxidase (MAO) inhibitors or within 2 weeks of discontinuation of treatment with MAO (see section 4.5) • patients with phaeochromocytoma. Morphine and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release • acute asthma exacerbations (see section 4.4 for information relating to use in controlled asthma)

The medicine should be used carefully in the following patient groups:
• in the first 24 hours post-operatively
• in hypothyroidism (see section 4.2)

• In patients with obstructive respiratory disorders, reduced respiratory reserve (e.g. kyphoscoliosis, emphysema, cor pulmonale or severe obesity)
Asthma
It has been suggested that opioids can be used with caution in controlled asthma. However, opioids are contraindicated in acute asthma exacerbations (see section 4.3).
Head injury and increased intracranial pressure
Oramorph is contraindicated in patients with increased intracranial pressure, head injuries and coma (see section 4.3). The capacity of morphine to elevate cerebrospinal fluid pressure may be greatly increased in the presence of already elevated intracranial pressure produced by trauma. Also, morphine may produce confusion, miosis, vomiting and other adverse reactions which may obscure the clinical course of patients with head injury.
Abdominal conditions
Morphine sulfate must not be given if paralytic ileus is likely to occur (see section 4.3), or if the patient has bowel or obstructive biliary disease. Should paralytic ileus be suspected or occur during use, Oramorph should be discontinued immediately.
Caution should be exercised where there is an obstructive bowel disorder, biliary colic, operations on the biliary tract, acute pancreatitis or prostatic hyperplasia.
If constipation occurs this may be treated with the appropriate laxatives.
Care should be exercised in patients with inflammatory bowel disease.
Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and complications following abdominal surgery.
Hypotensive effect
The administration of morphine can lead to a severe decrease in blood pressure in patients with impaired capability of maintaining homeostatic blood pressure e.g. decreased blood volume, concomitant administration of phenothiazines or certain anaesthetics (see section 4.5).
Drug dependence, tolerance and potential for abuse
Morphine sulfate is an opioid agonist and controlled drug.
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.
Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Morphine sulfate may be abused by inhaling or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.
Patients should be closely monitored for signs of misuse, abuse, or addiction.

Morphine has an abuse potential similar to other strong agonist opioids, and should be used with particular caution in patients with a history of alcohol or drug abuse.
The clinical need for analgesic treatment should be reviewed regularly.
Drug withdrawal syndrome
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with Oramorph.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
Hyperalgesia
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain.
Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses. A morphine dose reduction or change in opioid may be required.
Hypersensitivity
Hypersensitivity and anaphylactic reactions have both occurred with the use of Oramorph. Care should be taken to elicit any history of allergic reactions to opiates. Oramorph is contraindicated in patients known to be hypersensitive to morphine sulfate (see section 4.3).
Adrenal insufficiency
Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.
Decreased sex hormones and increased prolactin
Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.
Risk in special populations
Morphine is metabolised by the liver and should be used with caution in patients with hepatic disease as oral bioavailability may be increased. It is wise to reduce dosage in chronic hepatic and renal disease, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy or shock (see section 4.2).
The active metabolite Morphine-6-glucuronide may accumulate in patients with renal failure, leading to CNS and respiratory depression.
Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)
Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted.
Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs
Concomitant use of Oramorph and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death.

Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Oramorph concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
Oral P2Y12 inhibitor antiplatelet therapy
Within the first day of concomitant P2Y12 inhibitor (e.g. clopidogrel, prasugrel, ticagrelor) and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5).
Excipient related warnings
This medicine also contains 1 mg sodium benzoate (E211) in each 1 ml. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
This medicine contains less than 1 mmol sodium (23 mg) per ml (16 drops), that is to say essentially ‘sodium-free’.

Monoamine oxidase inhibitors
Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis, therefore their concomitant use with Oramorph is contraindicated (see section 4.3).
Gabapentin
Interactions have been reported in those taking morphine and gabapentin concomitantly. Reported interactions suggest an increase in opioid adverse events, the mechanism of which is not known. Caution should be taken where these medicines are prescribed concomitantly.
In a study involving healthy volunteers (N=12), when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.
Ritonavir
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir may increase the activity of glucuronyl transferases. Consequently, co- administration of ritonavir and morphine may result in decreased serum concentrations of morphine with possible loss of analgesic effectiveness.
Rifampicin
Rifampicin can reduce the serum concentration of morphine and decrease its analgesic effect, the mechanism of which is not known.
The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.
Cimetidine
Cimetidine inhibits the metabolism of morphine.
CNS depressants
The concomitant application of tranquilisers, anaesthetics (see section 4.4), sedatives, antipsychotics, tricyclic antidepressants, and alcohol increases the CNS depressing effect of morphine, especially the depressive effect on respiration.

Sedative medicines such as benzodiazepines or related drugs
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
Esmolol
Morphine may increase plasma concentrations of esmolol.
Domperidone/metoclopramide
Opioid analgesics including morphine may antagonise the actions of domperidone and metoclopramide on gastro-intestinal activity.
Mexiletine
The absorption of mexiletine may be delayed by concurrent use of morphine.
Phenothiazine antiemetics
Phenothiazine antiemetics may be given with morphine. However, hypotensive effects have to be considered (see section 4.4).
Oral Anticoagulants
A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced P2Y12 inhibitor efficacy in patients co-administered morphine and a P2Y12 inhibitor (see section 4.4).
In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Pregnancy
Although morphine sulfate has been in general use for many years, there is inadequate evidence of safety in human pregnancy.
Morphine is known to cross the placenta. Therefore, Oramorph should not be used in pregnancy, especially the first trimester unless the expected benefit is thought to outweigh any possible risk to the foetus.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
The risk of gastric stasis and inhalation pneumonia is increased in the mother during labour. Since morphine rapidly crosses the placental barrier it should not be used during the second stage of labour or in premature delivery because of the risk of secondary respiratory depression in the newborn infant.
Breast-feeding
Although morphine sulfate has been in general use for many years, there is inadequate evidence of safety during lactation.

Administration to nursing women is not recommended as morphine sulphate may be secreted in breast milk and may cause respiratory depression in the infant.
Fertility
Long term use of opioid analgesics can cause hypogonadism and adrenal insufficiency in both men and women. This is thought to be dose related and can lead to amenorrhoea, reduced libido, infertility and erectile dysfunction.
Animal studies have shown that morphine may reduce fertility (see 5.3. preclinical safety data).

Oramorph has major influence on the ability to drive and use machines, as it may cause drowsiness and reduce alertness. This is to be expected especially upon initiation of treatment, dose increase and change in medication as well as in combination with alcohol and centrally depressing substances.
Patients should not drive or use machines while taking Oramorph.
The time after which such activities may be safely resumed is extremely patient-dependent and must be decided by the physician.

In normal doses, the commonest side effects of morphine sulfate are nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives. The effects of morphine have led to its abuse and misuse. Dependence and addiction may develop with regular use.
Data from clinical trials are not available. Therefore it is not possible to provide information on the frequencies of undesirable effects, except where stated. A full list of currently known adverse reactions is presented below:

SOC Category	Side effect
Immune system disorders	Hypersensitivity Anaphylactic reaction (see section 4.4) Anaphylactoid reactions
Psychiatric disorders	Confusional state Restlessness Altered mood Hallucination Dependence (see section 4.4)
Nervous system disorders	Somnolence Headache Increased intracranial pressure (see section 4.4) Allodynia Hyperalgesia (see section 4.4)
Eye Disorders	Miosis
Ear and labyrinth disorders	Vertigo
Respiratory, thoracic and mediastinal disorders	Respiratory depression (see section 4.4 and section 4.6)
Cardiac disorders	Bradycardia Tachycardia Palpitations
Vascular disorders	Hypotension Flushing
Gastrointestinal disorders	Nausea Vomiting Constipation (see section 4.4) Dry mouth
General disorders and administration site conditions	Hypothermia Drug tolerance (see section 4.4) Drug withdrawal syndrome* (see section 4.4 and section 4.6)
Hepatobiliary Disorders	Biliary colic
Skin and subcutaneous tissue disorders	Urticaria Pruritus Hyperhidrosis
Musculoskeletal and connective tissue disorders	Muscle rigidity
Renal and urinary disorders	Dysuria Ureteral spasm Oliguria
Reproductive system and breast disorders	Decreased libido Erectile dysfunction

*Frequency uncommon (≥ 1/1,000 to < 1/100)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any side effect(s):
• Saudi Arabia:
-The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States:
-Please contact the relevant competent authority.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.
Symptoms:
Signs of morphine toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and hypotension.
Circulatory failure, pneumonia aspiration and deepening coma may occur in more severe cases.
Convulsions may occur in infants and children.
Death may occur from respiratory failure.
Treatment
Adults: Administer 0.4-2 mg of naloxone intravenously. Repeat at 2-3 minute intervals as necessary to a maximum of 10 mg, or by 2 mg in 500 ml of normal saline or 5 % dextrose (4 micrograms/ml).
Children: 5-10 micrograms per kilogram body weight intravenously. If this does not result in the desired degree of clinical improvement, a subsequent dose of 100 mcg/kg body weight may be administered.
Care should always be taken to ensure that the airway is maintained. Assist respiration if necessary.
Maintain fluid and electrolyte levels. Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated. Peak plasma concentrations of morphine are expected to occur within 15 minutes of oral ingestion. Therefore gastric lavage and activated charcoal are unlikely to be beneficial.
Caution: the duration of the effect of naloxone (2-3 hours) may be shorter than the duration of the effect of the morphine overdose. It is recommended that a patient who has regained consciousness after naloxone treatment should be observed for at least 6 hours after the last dose of naloxone.

Pharmacotherapeutic group: Natural opium alkaloids
ATC code: N02AA01
Morphine binds to specific receptors located in the CNS and in various peripheral organs. Pain sensation and affective reaction to the pain is reduced by interaction with CNS receptors.

Absorption
Morphine sulfate is readily absorbed from the gastrointestinal tract following oral administration. Following oral administration of radiolabelled morphine sulfate to humans, peak plasma levels were reached after approximately 15 minutes. Morphine undergoes significant first pass metabolism in the liver resulting in a systemic bioavailability of approximately 25% (range 15-49%).
Distribution
Morphine is distributed throughout the body but found mainly in the kidneys, liver, lung and spleen with lower concentrations being found in the brain and muscles. Approximately one third of morphine in the plasma is protein bound after a therapeutic dose. Morphine diffuses across the placenta and traces of the drug appear in breast milk.
Biotransformation
Metabolism of morphine principally involves conjugation to morphine 3- and 6- glucuronides. Small amounts are also metabolised by N-demethylation and O-methylation. Morphine-6- glucuronide has pharmacological effects indistinguishable from those of morphine. The half-life of morphine is approximately 2 hours. The half-life of morphine-6-glucuronide is somewhat longer.
Elimination
About 10 % of a dose of morphine is excreted through the bowel into the faeces. The remainder is excreted in the urine, mainly in the form of conjugates. About 90 % of a single dose of morphine is excreted in 24 hours. Enterohepatic circulation of morphine and its metabolites can occur, and may result in small quantities of morphine being present in the urine or faeces several days after the last dose.

In male rats, reduced fertility and chromosomal damage in gametes have been reported.

Disodium edetate
Sodium benzoate (E 211)
Citric acid
Purified water

Not applicable.

24 months. Shelf-life after first opening: 3 months.

Do not store above 30°C.
Once the bottle is opened, store below 25°C.
Keep the product in the original package to protect it from the light.

Amber coloured glass (type III Ph.Eur.) bottle with 20 ml of oral solution, closed with tamper evident child resistant HDPE screw cap and integrated LDPE dropper.

The unused product must be disposed off in accordance with the local requirements.